Recent advances in neuroscience are making clear the natural shape of neurotransmitters, substances deeply related to memory in brain. It is said that some of these substances are neuropeptides containing prolines.
Recovery of the memory was reported by the dosage of a neuropeptide containing proline to an experimental amnesia rat (See Science 211, 601 (1981)).
On the other hand, it is presumed that these neuropeptide - hormons shall be metabolized by cerebral endogenous peptidases. Especially, prolyl endopeptidase (EC, 3. 4. 21. 26) might intimately take part in such metabolism closely (See J. Biochem., 94, 1179 (1983)).
From these facts, studies were in progress based on the conclusion that it should be possible to prevent or treat amnesia by inhibiting prolyl endopeptidase and suppressing the metabolism of neutrotransmitter. (See Protein, Nucleic acid and Enzyme 25(6), 513(1980); Nippon Nougei Kagaku Kaishi 58(11), 1147(1984); J. Neurochem., 41, 69(1983); ibid 42, 237(1984).)
For the purpose described above, several compounds were synthesized. For example, it is clear that N-benzyloxycarbonyl-glycyl-L-prolyl-chloromethane, N-benzyloxycarbonyl-L-propyl-prolinal strongly inhibits prolyl endopeptidase (See J. Neurochem., 41, 69 (1983)). More recently, it is disclosed that the compounds shown below are effective for the above purpose.
(i) Prolinal derivatives of the general formula: ##STR3## wherein A represents a protecting group of amino acid group in the field of amino acid chemical, and X represents a residual group of amino acid. See Japanese Patent Kokai No. 60-188317, i.e., European Patent Publication No. 154353.
(ii) N-acylpyrrolidine derivatives of the general formula: ##STR4## wherein n represents a number of 1.about.4, and R represents lower alkyl ester group, --CH.sub.2 OH group or aldehyde group.
See Japanese Patent Kokai No. 61-37764; a compound wherein n is 5 is also disclosed by correction, i.e., European Patent Publication No. 172458.
(iii) Compounds of the general formula: ##STR5## wherein A represents methyl group or benzyloxy group, R represents isopropyl group or isobutyl group on the condition that plural R's have the same meaning in one formula. And n represents 2 or 3.
See Japanese Patent Kokai No. 61-183297.
Most recently, five applications related to anti-amnesia agents having prolinal skeltons were published, i.e.:
(iv) Compounds of the general formula: ##STR6## wherein R represents a group of ##STR7##
See Japanese Patent Kokai No. 61-238775, i.e., European Patent Publication No. 201741.
(v) N-acylpyrrolidine derivatives of the general formula: ##STR8## wherein R.sup.3 represents lower alkyloxycarbonyl group, hydroxymethyl group or formyl group, R.sup.1 represents a hydrogen atom or lower alkyl group, R.sup.2 represents phenyl group or a group of the following general formula: ##STR9## wherein R.sup.4 represents a hydrogen atom, a halogen atom or lower alkoxy group, R.sup.5 represents a hydrogen atom or lower alkyl group, n represents 1 or 1, A represents an oxygen atom, methylene group, hydroxymethylene group, phenylmethylene group or carbonyl group. or R.sup.1 and R.sup.2 represent, together with, benzylidene group unsubstituted or substituted by aromatic ring(s).
See Japanese Patent Kokai No. 61-238776, i.e., European Patent Publication No. 201742.
(vi) Compounds of the general formula: ##STR10## wherein n represents a number of 0.about.2, R.sup.1 represents a straight-chained organic group of from 5 to 25 carbon atoms which is saturated or unsaturated, wherein an unsaturated carbon chain may contain a plural number of double bonds, R.sup.2 represents a group of ##STR11## and R.sup.3 represents lower alkyl ester group, --CH.sub.2 OH group or aldehyde group. See Japanese Patent Kokai No. 61-238799, i.e., European Patent Publication No. 201743.
(vii) Compounds of the general formula: ##STR12## wherein n is an integer of more than one, R.sub.1 is a saturated or unsaturated straight-chained hydrocarbon group of from 5 to 25 carbon atoms, wherein said unsaturated carbon chain may contain a plural number of double bonds, R.sup.3 represents lower alkyl ester group of the formula: --COOR.sup.4 (wherein R.sup.4 represents lower alkyl group, hydroxymethyl group or formyl group, R.sup.2 represents methyl group, phenyl group, hydroxyphenyl group, indolyl group, imidazolyl group, carboxyl group, formyl group, amino group, hydroxy group, hydroxyalkyl group, thiol group, methylothio group or guanidino group etc., and each of above groups may be substituted and R.sup.5 represents a hydrogen atom or a single bond between a carbon atom and nitrogen atom together with R.sup.2 when n is 3.
See Japanese Patent Kokai No. 62-84058, i.e. European Patent Publication No. 201743.
(viii) Dipeptide derivatives of the general formula: ##STR13## wherein m represents an integer of 1.about.8, n represents an integer of 1.about.6, R.sup.1 represents a hydrogen atom, R.sup.2 represents a hydrogen atom, a branched alkyl group of from 3 to 5 carbon atoms, phenyl group, hydroxyphenyl group, indolyl group, imidazolyl group or methylthio group, or a single bond between a carbon atom and a nitrogen atom together with R.sup.1 and R.sup.3 represents lower alkyl ester group, hydroxymethy group or formyl group.
See Japanese Patent Kokai No. 62-148467, i.e., European Patent Publication No. 201741.
The present inventors have also filed an application related to prolinal derivatives having an anti amnesia activity, in advance of the present application, i.e.
(ix) Prolinal derivatives of the general formula: ##STR14## wherein A represents alkylene or alkenylene group of from 1 to 8 carbon atom(s) or a saturated hydrocarbon ring of from 3 to 7 carbon atoms, R represents a hydrogen atom, phenyl group, benzyl group, alkyl group of from 1 to 8 carbon atoms(s) or cycloalkyl group of from 3 to 7 carbon atoms, B represents alkylene group of from 1 to 8 atoms(s) unsubstituted or substituted by phenyl group or benzyl group, or a single bond, D represents carbocyclic or heterocyclic ring unsubstituted or substituted by from one to three of halogen atom, alkyl or alkoxy group of from 1 to 4 carbon atom(s), nitro group or trifluoromethyl group.
See Japanese patent Kokai No. 62-290631, i.e., European Patent Application No. 87116613.8.